TY - JOUR
T1 - Stromal Versican Regulates Tumor Growth by Promoting Angiogenesis
AU - Asano, Keiichi
AU - Nelson, Courtney M.
AU - Nandadasa, Sumeda
AU - Aramaki-Hattori, Noriko
AU - Lindner, Daniel J.
AU - Alban, Tyler
AU - Inagaki, Junko
AU - Ohtsuki, Takashi
AU - Oohashi, Toshitaka
AU - Apte, Suneel S.
AU - Hirohata, Satoshi
N1 - Funding Information:
We dedicate this paper to the late Professor Dr. Yoshifumi Ninomiya for leading us to this research field. We also thank Ms. Miki Taga, Drs. Tomoko Yonezawa, Mitsuaki Ono, Midori Edamatsu, Takahiro Maeba, Shozo Kusachi, Omer F. Hatipoglu, Mefmet Z. Cilek and Matthias Hofmann for technical advice and critical suggestions. This work was supported in part by grants-in-aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS KAKENHI Grant Numbers 17H04313 and 17K19727 to SH, 16K10905 to TO) and an award from the NIH-NHLBI Program of Excellence in Glycosciences (HL107147 to SA).
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - The proteoglycan versican is implicated in growth and metastases of several cancers. Here we investigated a potential contribution of stromal versican to tumor growth and angiogenesis. We initially determined versican expression by several cancer cell lines. Among these, MDA-MB231 and B16F10 had none to minimal expression in contrast to Lewis lung carcinoma (LLC). Notably, tumors arising from these cell lines had higher versican levels than the cell lines themselves suggesting a contribution from the host-derived tumor stroma. In LLC-derived tumors, both the tumor and stroma expressed versican at high levels. Thus, tumor stroma can make a significant contribution to tumor versican content. Versican localized preferentially to the vicinity of tumor vasculature and macrophages in the tumor. However, an ADAMTS protease-generated versican fragment uniquely localized to vascular endothelium. To specifically determine the impact of host/stroma-derived versican we therefore compared growth of tumors from B16F10 cells, which produced littleversican, in Vcan hdf/+ mice and wild-type littermates. Tumors in Vcan hdf/+ mice had reduced growth with a lower capillary density and accumulation of capillaries at the tumor periphery. These findings illustrate the variability of tumor cell line expression of versican, and demonstrate that versican is consistently contributed by the stromal tissue, where it contributes to tumor angiogenesis.
AB - The proteoglycan versican is implicated in growth and metastases of several cancers. Here we investigated a potential contribution of stromal versican to tumor growth and angiogenesis. We initially determined versican expression by several cancer cell lines. Among these, MDA-MB231 and B16F10 had none to minimal expression in contrast to Lewis lung carcinoma (LLC). Notably, tumors arising from these cell lines had higher versican levels than the cell lines themselves suggesting a contribution from the host-derived tumor stroma. In LLC-derived tumors, both the tumor and stroma expressed versican at high levels. Thus, tumor stroma can make a significant contribution to tumor versican content. Versican localized preferentially to the vicinity of tumor vasculature and macrophages in the tumor. However, an ADAMTS protease-generated versican fragment uniquely localized to vascular endothelium. To specifically determine the impact of host/stroma-derived versican we therefore compared growth of tumors from B16F10 cells, which produced littleversican, in Vcan hdf/+ mice and wild-type littermates. Tumors in Vcan hdf/+ mice had reduced growth with a lower capillary density and accumulation of capillaries at the tumor periphery. These findings illustrate the variability of tumor cell line expression of versican, and demonstrate that versican is consistently contributed by the stromal tissue, where it contributes to tumor angiogenesis.
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U2 - 10.1038/s41598-017-17613-6
DO - 10.1038/s41598-017-17613-6
M3 - Article
C2 - 29222454
AN - SCOPUS:85042385173
VL - 7
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 17225
ER -